HCV infects 170 million persons worldwide and causes significant morbidity in developed and developing countries. Therapies for HCV infection have improved recently, but still fail in many persons and are unavailable for most infected individuals worldwide. Therefore understanding natural immunity to this infection and the development of prophylactic vaccines and immunotherapies remain urgent goals. To this end, it will be essential to better understand the earliest events during acute HCV infection, as this is the exclusive time at which spontaneous clearance of viremia has been observed to occur. Over the previous funding period our center has been successful in collaboratively gaining new insights into various aspects of acute HCV infection, based on strong clinical cohorts and synergistic research projects. We have established two large cohorts of subjects with acute HCV infection contributing samples from highly complementary patient profiles that have allowed multiple successful collaborative projects, within and beyond the Center. At the National Reference Center for Viral Hepatitis at the Oswaldo Cruz Institute in Rio de Janeiro/Brazil we identify cases of acute symptomatic HCV with a high natural clearance rate and with unique success rates in long-term follow up of subjects. In Massachusetts we are studying the problem of acute HCV infection in recently incarcerated intravenous drug users, an important underserved population with a high risk of HCV exposure. The success of both cohorts allows us to carefully tailor the appropriate study population to each scientific question we want to address. To study the mechanisms leading to viral eradication or persistence we have developed novel highly sensitive and specific immunologic assays that allow for an unprecedented comprehensive assessment of NK cells and HCV-specific T-cell immune responses. Our approaches allow us to move beyond purely descriptive studies in humans to gain mechanistic insights in the correlates of protection and mechanisms of viral escape. We have also initiated multiple collaborations beyond the core members of this Center to investigate additional mechanisms not covered here, e.g. the role of neutralizing antibodies. In summary, we will collect comprehensive clinical, immunological and virological data from a large group of individuals with acute HCV infection, representing different routes of transmission, different clinical presentations and different outcomes of infection. We are confident that the comprehensive description of the complex interactions between human immune system and the virus will result in a significantly improved understanding of the mechanisms involved in viral control and persistence and will facilitate future preventative and therapeutic interventions against HCV infection.